Sherry Parker, Ph.D. and Bob Pryzgoda, Ph.D.09.01.20
Even with the delay of the European Union’s Medical Device Regulation (MDR) deadline until May 26, 2021, the race to reach compliance is still on for medical device manufacturers. The preparation and implementation processes are still extremely rigorous and time-consuming, and COVID-19 has caused additional strains for Notified Bodies (NB).
Manufacturers need to prepare to navigate these conditions efficiently while readying devices for submission, leaving no room for error. They have to know all the minor ins and outs of the MDR to ensure submissions are compliant and completed on time. There are often overlooked facts to consider when preparing an MDR submission that can help manufacturers minimize risk and pass their submissions with flying colors.
Compliant Data vs. State-of-the-Art
While it is required for companies to submit complete data packages for all devices aiming to remain on the EU market, additional testing may not be necessary to satisfy the expectation that all device evaluations meet current standards as required under the MDR. Regulators will accept tests and evaluations that do not meet current standards if any gaps identified in the tests or evaluations can be justified as meeting MDR requirements. Manufacturers have until May 27, 2024, to comply with this requirement.
The legal formalities of accepting new or revised standards in the EU can be time-consuming and cumbersome. Standards that are legally accepted by all EU countries are referred to as harmonized standards. Device evaluation requirements must meet the expectations set by harmonized standards. Still, regulatory reviewers may expect testing to meet ISO-approved standards that are not yet harmonized to be used in the evaluations because these standards are considered state-of-the-art. The challenge for manufacturers is balancing when to use data that only comply with current harmonized standards and when it is worth the extra time to generate data that will meet the state-of-the-art unharmonized ISO standards.
Broadly, there have not been numerous changes to biocompatibility standards and most of the testing methods are still sound. Some manufacturers can satisfy MDR testing requirements without having to do any additional biocompatibility testing. One area for consideration during submission preparation is the expectation to limit the use of in vivo testing. Unnecessary in vivo testing may place submissions in a negative light for EU regulators. If in vivo testing is necessary for specific devices, it may be beneficial to look into whether past data is still compliant to avoid the need for further testing.
The most significant testing changes are associated with chemical characterization. ISO 10993-18:2020, while not harmonized, now represents the state-of-the-art for chemical analysis. The previous harmonized version of ISO 10993-18 provided limited guidance. However, it is unlikely that past data—possibly even testing from 2019 to prepare for the MDR—comes close to offering the same in-depth quality of data generation and evaluation as the 2020 version. New updates to the standard include several definitions and annexes to lend consistency to industry-wide chemical characterization. Although ISO 10993-18 added a significant level of detail, it does not offer clear test methods for conducting chemical characterization, which is why it will be essential to work with a lab testing partner to provide state-of-the-art analysis.
Furthermore, ISO 10993-17 is in development, with the current goal of publication going into effect in 2021. Part 17 will require a thorough and defendable toxicological risk assessment. Some regulators are already expecting some of the requirements in this revised standard to be met. Once this standard is ISO approved, any risk assessment using the current part 17 standard will likely need to be revised. It is worth investing in preparing that risk assessment now since the implementation date is fast approaching. In these assessments, manufacturers must make expert judgment calls and defend them to regulators. Work with a lab testing partner to get comfortable performing and defending risk assessments now for long-term success.
Rigorous Testing for Short-Term Devices
Under the Medical Device Directive (MDD), the contact duration of a device played a critical role in determining testing requirements. The testing results for transient exposure devices would not face the same level of scrutiny for carcinogenic, mutagenic, or toxic to reproduction substances (CRM substances) as long-term duration devices. However, under the MDR, any invasive device, including those with less than 24 hours of patient contact, will require knowledge of any CMRs present in device components at a concentration equal to or greater than 0.1 percent. If this information is not available, NBs will likely direct manufacturers back to chemistry testing to find answers. If CMRs are present in device components, a risk assessment and justification for continued use of the material will be required.
Toxicologists and regulatory bodies are consistently updating the CRM substance list, so it is advantageous to work with a lab that can help manufacturers stay informed and updated on the chemicals that cause red flags during submission review.
What Supply Chain Disruptions Mean for New Materials
Due to supply chain strains caused by COVID-19, acquiring raw materials promptly and in the correct quantity can be challenging. Manufacturers are now reconsidering their device materials and go-to suppliers. Some are even discovering their back-up material choice is no longer an option, forcing them to go further down their list of preferences.
More suppliers are facing pressure to undergo chemistry testing for materials in new applications to ensure they are sufficient quality or considered medical grade. Using a supplier that provides detailed information on their materials is preferable, especially with the pressure to recognize the presence of CMR substances in a greater pool of devices. The same testing requirements for CMR substances must be in place for alternative suppliers, leading to more chemical testing to comply with the MDR.
Biocompatibility Specialists in Short Supply
The demand for biocompatibility specialists is high, which may make finding qualified experts difficult. The medical device industry is transitioning to the MDR requirements and the increased work to achieve this is putting a significant amount of stress on the labor market. Manufacturers must employ biocompatibility specialists for both normal operations and MDR operations, meaning there is limited capacity both internally and with contracted partners. As a result, some manufacturers have taken to pushing quality engineers and regulatory experts into roles to which they are not adept.
The best solution is to plan accordingly and identify where additional support could be beneficial early in project development. The biggest mistake a manufacturer can make is not planning appropriately and consequently scrambling to find resources at the last minute. Start testing early and make the necessary investments to complete a comprehensive device assessment that complies with MDR requirements.
Developing a Submission Plan
Limits to capacity are not only affecting internal manufacturing teams but also outsourced testing partners, since more device manufacturers are turning to them for testing and guidance. Some contract research organizations have expanded their bandwidth for MDR preparation. Still, there are no guarantees they will be able to meet everyone’s needs against the compliance timelines. The longer companies wait to communicate their submission strategy and preparation timeline with testing labs, the longer it will take to work their way to the front of the line.
The best strategy for getting on a testing partner’s schedule is prepare a plan aligned to the MDR regulatory submission timeline. Labs are more likely to accommodate those who have a plan and can prioritize their portfolios. Without a plan, companies risk having insufficient data that could cause a significant setback.
Less Room for Error
There are only 15 MDR approved NBs, a substantial decrease compared to the number NBs under the MDD. And once the MDR approves a NB, it will no longer accept submissions under the MDD. On top of that, COVID-19 has slowed down the entire review process. Even with the MDR application extension, the transition is still moving at a slow pace. Currently, NBs are focusing on the influx of critical work needed for Personal Protective Equipment to keep enough of these critical devices on the market to address the pandemic.
With a limited number of NBs stretched to capacity, there is a limited amount of time to review each submission and provide feedback. There is no guarantee they’ll provide in-depth details about submission errors if something is incomplete. Instead, they may require more information and send companies to the back of the line for review. NBs will likely show a preference for manufacturers that provide detailed information, including labeling for CMR substances. Additionally, working with a third-party testing partner can also help build credibility in a reviewer’s eye.
MDR readiness is a challenge and it feels like there is always more to learn, especially with the impact of COVID-19 changing the world by the minute. It is best to approach the process with the intention to over-prepare. By investing upfront in proper chemical characterization, skilled labor, supply chain alternative, and a knowledgeable testing partner, manufacturers can avoid lost time on the market and high costs later on.
Dr. Sherry Parker has over 20 years of toxicology and medical device experience, and is an expert in analytical, pharmacological, and toxicological evaluations of medical devices and combination products. After receiving her Ph.D. in molecular and cellular pharmacology from the University of Miami, Dr. Parker worked as a toxicologist for the U.S. EPA, RTI International, OrbusNeich Medical, and Fresenius Medical Care. In her current position at WuXi AppTec, Dr. Parker guides manufacturers on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Advancing Safety in Health Technology / Biological Evaluation Committee.
For 15 years, Dr. Robert T. Przygoda served as both the manager of the Genetic Toxicology Group and the study director for Genetic Toxicity Tests at Exxon Biomedical Sciences. He chaired the American Industrial Health Council’s Mutagenicity Sub-Committee from 1992-1994. Dr. Przygoda was elected to the Board of Directors from 1996 - 2000. From 1999 – 2000 he was the president of the Genetic Toxicology Association. In 1999, Dr. Przygoda joined Ethicon Endo-Surgery, a Johnson & Johnson Company, where he assisted in the development of the medical device biocompatibility evaluation program. Dr. Przygoda received his Ph.D. in microbiology and molecular genetics from Rutgers University and the UMDNJ.
Manufacturers need to prepare to navigate these conditions efficiently while readying devices for submission, leaving no room for error. They have to know all the minor ins and outs of the MDR to ensure submissions are compliant and completed on time. There are often overlooked facts to consider when preparing an MDR submission that can help manufacturers minimize risk and pass their submissions with flying colors.
Compliant Data vs. State-of-the-Art
While it is required for companies to submit complete data packages for all devices aiming to remain on the EU market, additional testing may not be necessary to satisfy the expectation that all device evaluations meet current standards as required under the MDR. Regulators will accept tests and evaluations that do not meet current standards if any gaps identified in the tests or evaluations can be justified as meeting MDR requirements. Manufacturers have until May 27, 2024, to comply with this requirement.
The legal formalities of accepting new or revised standards in the EU can be time-consuming and cumbersome. Standards that are legally accepted by all EU countries are referred to as harmonized standards. Device evaluation requirements must meet the expectations set by harmonized standards. Still, regulatory reviewers may expect testing to meet ISO-approved standards that are not yet harmonized to be used in the evaluations because these standards are considered state-of-the-art. The challenge for manufacturers is balancing when to use data that only comply with current harmonized standards and when it is worth the extra time to generate data that will meet the state-of-the-art unharmonized ISO standards.
Broadly, there have not been numerous changes to biocompatibility standards and most of the testing methods are still sound. Some manufacturers can satisfy MDR testing requirements without having to do any additional biocompatibility testing. One area for consideration during submission preparation is the expectation to limit the use of in vivo testing. Unnecessary in vivo testing may place submissions in a negative light for EU regulators. If in vivo testing is necessary for specific devices, it may be beneficial to look into whether past data is still compliant to avoid the need for further testing.
The most significant testing changes are associated with chemical characterization. ISO 10993-18:2020, while not harmonized, now represents the state-of-the-art for chemical analysis. The previous harmonized version of ISO 10993-18 provided limited guidance. However, it is unlikely that past data—possibly even testing from 2019 to prepare for the MDR—comes close to offering the same in-depth quality of data generation and evaluation as the 2020 version. New updates to the standard include several definitions and annexes to lend consistency to industry-wide chemical characterization. Although ISO 10993-18 added a significant level of detail, it does not offer clear test methods for conducting chemical characterization, which is why it will be essential to work with a lab testing partner to provide state-of-the-art analysis.
Furthermore, ISO 10993-17 is in development, with the current goal of publication going into effect in 2021. Part 17 will require a thorough and defendable toxicological risk assessment. Some regulators are already expecting some of the requirements in this revised standard to be met. Once this standard is ISO approved, any risk assessment using the current part 17 standard will likely need to be revised. It is worth investing in preparing that risk assessment now since the implementation date is fast approaching. In these assessments, manufacturers must make expert judgment calls and defend them to regulators. Work with a lab testing partner to get comfortable performing and defending risk assessments now for long-term success.
Rigorous Testing for Short-Term Devices
Under the Medical Device Directive (MDD), the contact duration of a device played a critical role in determining testing requirements. The testing results for transient exposure devices would not face the same level of scrutiny for carcinogenic, mutagenic, or toxic to reproduction substances (CRM substances) as long-term duration devices. However, under the MDR, any invasive device, including those with less than 24 hours of patient contact, will require knowledge of any CMRs present in device components at a concentration equal to or greater than 0.1 percent. If this information is not available, NBs will likely direct manufacturers back to chemistry testing to find answers. If CMRs are present in device components, a risk assessment and justification for continued use of the material will be required.
Toxicologists and regulatory bodies are consistently updating the CRM substance list, so it is advantageous to work with a lab that can help manufacturers stay informed and updated on the chemicals that cause red flags during submission review.
What Supply Chain Disruptions Mean for New Materials
Due to supply chain strains caused by COVID-19, acquiring raw materials promptly and in the correct quantity can be challenging. Manufacturers are now reconsidering their device materials and go-to suppliers. Some are even discovering their back-up material choice is no longer an option, forcing them to go further down their list of preferences.
More suppliers are facing pressure to undergo chemistry testing for materials in new applications to ensure they are sufficient quality or considered medical grade. Using a supplier that provides detailed information on their materials is preferable, especially with the pressure to recognize the presence of CMR substances in a greater pool of devices. The same testing requirements for CMR substances must be in place for alternative suppliers, leading to more chemical testing to comply with the MDR.
Biocompatibility Specialists in Short Supply
The demand for biocompatibility specialists is high, which may make finding qualified experts difficult. The medical device industry is transitioning to the MDR requirements and the increased work to achieve this is putting a significant amount of stress on the labor market. Manufacturers must employ biocompatibility specialists for both normal operations and MDR operations, meaning there is limited capacity both internally and with contracted partners. As a result, some manufacturers have taken to pushing quality engineers and regulatory experts into roles to which they are not adept.
The best solution is to plan accordingly and identify where additional support could be beneficial early in project development. The biggest mistake a manufacturer can make is not planning appropriately and consequently scrambling to find resources at the last minute. Start testing early and make the necessary investments to complete a comprehensive device assessment that complies with MDR requirements.
Developing a Submission Plan
Limits to capacity are not only affecting internal manufacturing teams but also outsourced testing partners, since more device manufacturers are turning to them for testing and guidance. Some contract research organizations have expanded their bandwidth for MDR preparation. Still, there are no guarantees they will be able to meet everyone’s needs against the compliance timelines. The longer companies wait to communicate their submission strategy and preparation timeline with testing labs, the longer it will take to work their way to the front of the line.
The best strategy for getting on a testing partner’s schedule is prepare a plan aligned to the MDR regulatory submission timeline. Labs are more likely to accommodate those who have a plan and can prioritize their portfolios. Without a plan, companies risk having insufficient data that could cause a significant setback.
Less Room for Error
There are only 15 MDR approved NBs, a substantial decrease compared to the number NBs under the MDD. And once the MDR approves a NB, it will no longer accept submissions under the MDD. On top of that, COVID-19 has slowed down the entire review process. Even with the MDR application extension, the transition is still moving at a slow pace. Currently, NBs are focusing on the influx of critical work needed for Personal Protective Equipment to keep enough of these critical devices on the market to address the pandemic.
With a limited number of NBs stretched to capacity, there is a limited amount of time to review each submission and provide feedback. There is no guarantee they’ll provide in-depth details about submission errors if something is incomplete. Instead, they may require more information and send companies to the back of the line for review. NBs will likely show a preference for manufacturers that provide detailed information, including labeling for CMR substances. Additionally, working with a third-party testing partner can also help build credibility in a reviewer’s eye.
MDR readiness is a challenge and it feels like there is always more to learn, especially with the impact of COVID-19 changing the world by the minute. It is best to approach the process with the intention to over-prepare. By investing upfront in proper chemical characterization, skilled labor, supply chain alternative, and a knowledgeable testing partner, manufacturers can avoid lost time on the market and high costs later on.
Dr. Sherry Parker has over 20 years of toxicology and medical device experience, and is an expert in analytical, pharmacological, and toxicological evaluations of medical devices and combination products. After receiving her Ph.D. in molecular and cellular pharmacology from the University of Miami, Dr. Parker worked as a toxicologist for the U.S. EPA, RTI International, OrbusNeich Medical, and Fresenius Medical Care. In her current position at WuXi AppTec, Dr. Parker guides manufacturers on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Advancing Safety in Health Technology / Biological Evaluation Committee.
For 15 years, Dr. Robert T. Przygoda served as both the manager of the Genetic Toxicology Group and the study director for Genetic Toxicity Tests at Exxon Biomedical Sciences. He chaired the American Industrial Health Council’s Mutagenicity Sub-Committee from 1992-1994. Dr. Przygoda was elected to the Board of Directors from 1996 - 2000. From 1999 – 2000 he was the president of the Genetic Toxicology Association. In 1999, Dr. Przygoda joined Ethicon Endo-Surgery, a Johnson & Johnson Company, where he assisted in the development of the medical device biocompatibility evaluation program. Dr. Przygoda received his Ph.D. in microbiology and molecular genetics from Rutgers University and the UMDNJ.
